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Developmental gene networks: a triathlon on the course to T cell identity

Key Points

  • T cell development depends on the regulated progression of progenitor cells through three major phases that are associated with distinct transcription factor ensembles and altered gene regulatory network states.

  • The first two phases are Notch dependent and T cell receptor (TCR) independent, whereas the third phase is TCR dependent and mediates the transition to Notch independence.

  • The first phase is dominated by legacy stem and progenitor cell gene regulatory networks that enable self-renewal and Notch-dependent expression of the first T cell-specific transcription factors, including GATA-binding protein 3 (GATA3) and T cell factor 1 (TCF1).

  • T cell lineage commitment — the loss of alternative latent developmental potentials — is triggered by induction of the phase 2 transcription factor B cell lymphoma–leukaemia 11B (BCL11B) and results in the downregulation of multiple progenitor-specific transcription factors.

  • In phase 2, T cell-specific regulators and Notch signalling drive the full activation of the T cell gene regulatory programme. TCR complex signalling components are expressed, TCR gene recombination is induced and TCR-dependent selection thresholds are imposed.

  • Transition from phase 2 to phase 3 depends on the expression and successful signalling of a pre-TCR or γδTCR. If successful, this switch from the phase 2 to phase 3 network triggers proliferation, loss of Notch dependency and dismantling of the Notch-dependent gene network.

  • Phase 1 legacy and stem cell transcription factors can become oncogenic if their expression is not correctly controlled. Cells that fail to fully shut off the expression of phase 1 regulators at the commitment and β-selection checkpoints — before the next phase of gene network expression is activated — may be predisposed to leukaemic transformation.

Abstract

Cells acquire their ultimate identities by activating combinations of transcription factors that initiate and sustain expression of the appropriate cell type-specific genes. T cell development depends on the progression of progenitor cells through three major phases, each of which is associated with distinct transcription factor ensembles that control the recruitment of these cells to the thymus, their proliferation, lineage commitment and responsiveness to T cell receptor signals, all before the allocation of cells to particular effector programmes. All three phases are essential for proper T cell development, as are the mechanisms that determine the boundaries between each phase. Cells that fail to shut off one set of regulators before the next gene network phase is activated are predisposed to leukaemic transformation.

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Figure 1: αβ T cell development: stages, surface markers and transcription factor expression.
Figure 2: T cell lineage commitment and alternative lineage potentials.
Figure 3: Current model for the progression of gene regulatory network states during T cell commitment.

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References

  1. Rothenberg, E. V., Moore, J. E. & Yui, M. A. Launching the T-cell-lineage developmental programme. Nature Rev. Immunol. 8, 9–21 (2008).

    CAS  Google Scholar 

  2. Petrie, H. T. & Zúñiga-Pflücker, J. C. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649–679 (2007).

    CAS  PubMed  Google Scholar 

  3. Thompson, P. K. & Zúñiga-Pflücker, J. C. On becoming a T cell, a convergence of factors kick it up a Notch along the way. Semin. Immunol. 23, 350–359 (2011).

    CAS  PubMed  Google Scholar 

  4. Yang, Q., Jeremiah Bell, J. J. & Bhandoola, A. T-cell lineage determination. Immunol. Rev. 238, 12–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Koch, U. & Radtke, F. Mechanisms of T cell development and transformation. Annu. Rev. Cell Dev. Biol. 27, 539–562 (2011).

    CAS  PubMed  Google Scholar 

  6. Love, P. E. & Bhandoola, A. Signal integration and crosstalk during thymocyte migration and emigration. Nature Rev. Immunol. 11, 469–477 (2011).

    CAS  Google Scholar 

  7. Lu, M. et al. The earliest thymic progenitors in adults are restricted to T, NK, and dendritic cell lineage and have a potential to form more diverse TCRβ chains than fetal progenitors. J. Immunol. 175, 5848–5856 (2005).

    CAS  PubMed  Google Scholar 

  8. Porritt, H. E., Gordon, K. & Petrie, H. T. Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J. Exp. Med. 198, 957–962 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Belyaev, N. N., Biro, J., Athanasakis, D., Fernandez-Reyes, D. & A. J. Global transcriptional analysis of primitive thymocytes reveals accelerated dynamics of T cell specification in fetal stages. Immunogenetics 64, 591–604 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Schmitt, T. M. & Zúñiga-Pflücker, J. C. Induction of T cell development from hematopoietic progenitor cells by Delta-like-1 in vitro. Immunity 17, 749–756 (2002). This paper transformed the field of early T cell development by creating a powerful and efficient in vitro system in which the developmental process can be observed and manipulated.

    CAS  PubMed  Google Scholar 

  11. Ng, S. Y., Yoshida, T., Zhang, J. & Georgopoulos, K. Genome-wide lineage-specific transcriptional networks underscore Ikaros-dependent lymphoid priming in hematopoietic stem cells. Immunity 30, 493–507 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Chi, A. W. et al. Identification of Flt3+CD150 myeloid progenitors in adult mouse bone marrow that harbor T lymphoid developmental potential. Blood 118, 2723–2732 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Krueger, A. & von Boehmer, H. Identification of a T lineage-committed progenitor in adult blood. Immunity 26, 105–116 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Boudil, A. et al. Single-cell analysis of thymocyte differentiation: identification of transcription factor interactions and a major stochastic component in αβ-lineage commitment. PLoS ONE 8, e73098 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Peaudecerf, L. et al. Thymocytes may persist and differentiate without any input from bone marrow progenitors. J. Exp. Med. 209, 1401–1408 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Martins, V. C. et al. Thymus-autonomous T cell development in the absence of progenitor import. J. Exp. Med. 209, 1409–1417 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Martins, V. C. et al. Cell competition is a tumour suppressor mechanism in the thymus. Nature 509, 465–470 (2014). References 15–17 overturned the long-standing theory that thymocytes cannot self-renew. They show that the loss of competition from fresh thymic immigrants leads to extensive self-renewal and allows oncogenic transformation of early stage thymocytes.

    CAS  PubMed  Google Scholar 

  18. Coustan-Smith, E. et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 10, 147–156 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012). References 18 and 19 characterize ETP-ALL, a high-risk human T-ALL subtype that is characterized by the expression of genes associated with the very earliest stages of normal T cell development.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Schlenner, S. M. et al. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity 32, 426–436 (2010).

    CAS  PubMed  Google Scholar 

  21. Luc, S. et al. The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential. Nature Immunol. 13, 412–419 (2012).

    CAS  Google Scholar 

  22. Serwold, T., Ehrlich, L. I. & Weissman, I. L. Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis. Blood 113, 807–815 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential: a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005).

    CAS  PubMed  Google Scholar 

  24. Heinzel, K., Benz, C., Martins, V. C., Haidl, I. D. & Bleul, C. C. Bone marrow-derived hemopoietic precursors commit to the T cell lineage only after arrival in the thymic microenvironment. J. Immunol. 178, 858–868 (2007).

    CAS  PubMed  Google Scholar 

  25. Radtke, F., Macdonald, H. R. & Tacchini-Cottier, F. Regulation of innate and adaptive immunity by Notch. Nature Rev. Immunol. 13, 427–437 (2013).

    CAS  Google Scholar 

  26. Rothenberg, E. V. T cell lineage commitment: identity and renunciation. J. Immunol. 186, 6649–6655 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Masuda, K. et al. T cell lineage determination precedes the initiation of TCRβ rearrangement. J. Immunol. 179, 3699–3706 (2007).

    CAS  PubMed  Google Scholar 

  28. Yui, M. A., Feng, N. & Rothenberg, E. V. Fine-scale staging of T cell lineage commitment in adult mouse thymus. J. Immunol. 185, 284–293 (2010). References 27 and 28 reveal the timing of T cell lineage commitment, showing its clear separation from TCR-dependent events and defining its basis in terms of changes in regulatory gene expression.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Taghon, T., Yui, M. A. & Rothenberg, E. V. Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nature Immunol. 8, 845–855 (2007).

    CAS  Google Scholar 

  30. Wong, S. H. et al. Transcription factor RORα is critical for nuocyte development. Nature Immunol. 13, 229–236 (2012).

    CAS  Google Scholar 

  31. Zhang, J. A., Mortazavi, A., Williams, B. A., Wold, B. J. & Rothenberg, E. V. Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity. Cell 149, 467–482 (2012). This paper presents the first genome-wide analysis of the epigenetic changes and transcriptional dynamics of early T cell development, using ChIP–seq and RNA sequencing assays across a succession of stages spanning T cell lineage commitment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mingueneau, M. et al. The transcriptional landscape of αβ T cell differentiation. Nature Immunol. 14, 619–632 (2013). This paper uses microarray analyses to show the transcriptomic changes that occur across an extended span of T cell development. Results were generated by the Immunological Genome Project, which is an invaluable publicly accessible source of gene expression data for all stages of immune cell development.

    CAS  Google Scholar 

  33. Hoffman, E. S. et al. Productive T-cell receptor β-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. Genes Dev. 10, 948–962 (1996).

    CAS  PubMed  Google Scholar 

  34. Taghon, T., Yui, M. A., Pant, R., Diamond, R. A. & Rothenberg, E. V. Developmental and molecular characterization of emerging β- and γδ-selected pre-T cells in the adult mouse thymus. Immunity 24, 53–64 (2006).

    CAS  PubMed  Google Scholar 

  35. Teague, T. K. et al. CD28 expression redefines thymocyte development during the pre-T to DP transition. Int. Immunol. 22, 387–397 (2010).

    CAS  PubMed  Google Scholar 

  36. Taghon, T. et al. Notch signaling is required for proliferation but not for differentiation at a well-defined β-selection checkpoint during human T-cell development. Blood 113, 3254–3263 (2009).

    CAS  PubMed  Google Scholar 

  37. Kreslavsky, T. et al. β-Selection-induced proliferation is required for αβ T cell differentiation. Immunity 37, 840–853 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ciofani, M., Knowles, G. C., Wiest, D. L., von Boehmer, H. & Zúñiga-Pflücker, J. C. Stage-specific and differential Notch dependency at the αβ and γδ T lineage bifurcation. Immunity 25, 105–116 (2006).

    CAS  PubMed  Google Scholar 

  39. Maillard, I. et al. The requirement for Notch signaling at the β-selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J. Exp. Med. 203, 2239–2245 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Garbe, A. I. & von Boehmer, H. TCR and Notch synergize in αβ versus γδ lineage choice. Trends Immunol. 28, 124–131 (2007).

    CAS  PubMed  Google Scholar 

  41. Kueh, H. Y. & Rothenberg, E. V. Regulatory gene network circuits underlying T cell development from multipotent progenitors. Wiley Interdiscip. Rev. Syst. Biol. Med. 4, 79–102 (2012).

    CAS  PubMed  Google Scholar 

  42. Naito, T., Tanaka, H., Naoe, Y. & Taniuchi, I. Transcriptional control of T-cell development. Int. Immunol. 23, 661–668 (2011).

    CAS  PubMed  Google Scholar 

  43. Mercer, E. M., Lin, Y. C. & Murre, C. Factors and networks that underpin early hematopoiesis. Semin. Immunol. 23, 317–325 (2011).

    PubMed  PubMed Central  Google Scholar 

  44. Rothenberg, E. V. Transcriptional drivers of the T-cell lineage program. Curr. Opin. Immunol. 24, 132–138 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. De Pooter, R. F. & Kee, B. L. E proteins and the regulation of early lymphocyte development. Immunol. Rev. 238, 93–109 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Braunstein, M. & Anderson, M. K. HEB in the spotlight: Transcriptional regulation of T-cell specification, commitment, and developmental plasticity. Clin. Dev. Immunol. 2012, 678–705 (2012).

    Google Scholar 

  47. Rothenberg, E. V., Zhang, J. & Li, L. Multilayered specification of the T-cell lineage fate. Immunol. Rev. 238, 150–168 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. David-Fung, E. S. et al. Transcription factor expression dynamics of early T-lymphocyte specification and commitment. Dev. Biol. 325, 444–467 (2009).

    CAS  PubMed  Google Scholar 

  49. Tabrizifard, S. et al. Analysis of transcription factor expression during discrete stages of postnatal thymocyte differentiation. J. Immunol. 173, 1094–1102 (2004).

    CAS  PubMed  Google Scholar 

  50. Kawazu, M. et al. Expression profiling of immature thymocytes revealed a novel homeobox gene that regulates double-negative thymocyte development. J. Immunol. 179, 5335–5345 (2007).

    CAS  PubMed  Google Scholar 

  51. Manesso, E., Chickarmane, V., Kueh, H. Y., Rothenberg, E. V. & Peterson, C. Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence. J. R. Soc. Interface 10, 20120774 (2013).

    PubMed  PubMed Central  Google Scholar 

  52. Gwin, K. A., Shapiro, M. B., Dolence, J. J., Huang, Z. L. & Medina, K. L. Hoxa9 and Flt3 signaling synergistically regulate an early checkpoint in lymphopoiesis. J. Immunol. 191, 745–754 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang, Y. et al. Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood 119, 388–398 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Riddell, J. et al. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157, 549–564 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yu, Y. et al. Bcl11a is essential for lymphoid development and negatively regulates p53. J. Exp. Med. 209, 2467–2483 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Capron, C. et al. The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation. Blood 107, 4678–4686 (2006).

    CAS  PubMed  Google Scholar 

  57. Souroullas, G. P., Salmon, J. M., Sablitzky, F., Curtis, D. J. & Goodell, M. A. Adult hematopoietic stem and progenitor cells require either Lyl1 or Scl for survival. Cell Stem Cell 4, 180–186 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zohren, F. et al. The transcription factor Lyl-1 regulates lymphoid specification and the maintenance of early T lineage progenitors. Nature Immunol. 13, 761–769 (2012).

    CAS  Google Scholar 

  59. McCormack, M. P. et al. Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL. Blood 122, 2093–2103 (2013).

    CAS  PubMed  Google Scholar 

  60. Lécuyer, E. et al. The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1. Blood 100, 2430–2440 (2002).

    PubMed  Google Scholar 

  61. Phelan, J. D. et al. Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genet. 9, e1003713 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Thoms, J. A. I. et al. ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer. Blood 117, 7079–7089 (2011).

    CAS  PubMed  Google Scholar 

  63. McCormack, M. P. et al. The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal. Science 327, 879–883 (2010). In this paper, the authors use fate mapping to demonstrate the role of Lmo2 in inducing self-renewal in early T cells, which can lead to leukaemia initiation. This role of Lmo2 is a prototype for linking natural thymocyte proliferative expansion with oncogenesis.

    CAS  PubMed  Google Scholar 

  64. Carotta, S., Wu, L. & Nutt, S. L. Surprising new roles for PU.1 in the adaptive immune response. Immunol. Rev. 238, 63–75 (2010).

    CAS  PubMed  Google Scholar 

  65. Dakic, A. et al. PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J. Exp. Med. 201, 1487–1502 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Del Real, M. M. & Rothenberg, E. V. Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3. Development 140, 1207–1219 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Heinz, S. et al. Effect of natural genetic variation on enhancer selection and function. Nature 503, 487–492 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ostuni, R. & Natoli, G. Lineages, cell types and functional states: a genomic view. Curr. Opin. Cell Biol. 25, 759–764 (2013).

    CAS  PubMed  Google Scholar 

  70. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    CAS  PubMed  Google Scholar 

  71. Visan, I. et al. Regulation of T lymphopoiesis by Notch1 and Lunatic fringe-mediated competition for intrathymic niches. Nature Immunol. 7, 634–643 (2006).

    CAS  Google Scholar 

  72. Georgescu, C. et al. A gene regulatory network armature for T lymphocyte specification. Proc. Natl Acad. Sci. USA 105, 20100–20105 (2008).

    CAS  PubMed  Google Scholar 

  73. Weng, A. P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20, 2096–2109 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, D. et al. The basic helix–loop–helix transcription factor HEBAlt is expressed in pro-T cells and enhances the generation of T cell precursors. J. Immunol. 177, 109–119 (2006).

    CAS  PubMed  Google Scholar 

  75. De Obaldia, M. E. et al. T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1. Nature Immunol. 14, 1277–1284 (2013).

    CAS  Google Scholar 

  76. Wendorff, A. A. et al. Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33, 671–684 (2010). References 75 and 76 demonstrate the crucial importance of Hes1 as a Notch target gene in the earliest stages of T cell development. Together these references show its discrete role in commitment (reference 75) and in normal population expansion, as well as in Notch-induced T-ALL (reference 76).

    CAS  PubMed  Google Scholar 

  77. Tomita, K. et al. The bHLH gene Hes1 is essential for expansion of early T cell precursors. Genes Dev. 13, 1203–1210 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Tsuji, M., Shinkura, R., Kuroda, K., Yabe, D. & Honjo, T. Msx2-interacting nuclear target protein (Mint) deficiency reveals negative regulation of early thymocyte differentiation by Notch/RBP-J signaling. Proc. Natl Acad. Sci. USA 104, 1610–1615 (2007).

    CAS  PubMed  Google Scholar 

  79. Yun, T. J. & Bevan, M. J. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. J. Immunol. 170, 5834–5841 (2003).

    CAS  PubMed  Google Scholar 

  80. Hosoya, T. et al. GATA-3 is required for early T lineage progenitor development. J. Exp. Med. 206, 2987–3000 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Germar, K. et al. T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling. Proc. Natl Acad. Sci. USA 108, 20060–20065 (2011).

    CAS  PubMed  Google Scholar 

  82. Miyazaki, M. et al. The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nature Immunol. 12, 992–1001 (2011).

    CAS  Google Scholar 

  83. Ikawa, T., Kawamoto, H., Goldrath, A. W. & Murre, C. E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment. J. Exp. Med. 203, 1329–1342 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Engel, I. & Murre, C. E2A proteins enforce a proliferation checkpoint in developing thymocytes. EMBO J. 23, 202–211 (2004).

    CAS  PubMed  Google Scholar 

  85. Jones-Mason, M. E. et al. E protein transcription factors are required for the development of CD4+ lineage T cells. Immunity 36, 348–361 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Jones, M. E. & Zhuang, Y. Acquisition of a functional T cell receptor during T lymphocyte development is enforced by HEB and E2A transcription factors. Immunity 27, 860–870 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Weber, B. N. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011). References 81 and 87 demonstrate that TCF1 is a key mediator of T cell specification that functions downstream of Notch signalling. Reference 87 shows that high levels of TCF1 drive the expression of T cell genes including Gata3 and Bcl11b even in the absence of Notch signals.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Tiemessen, M. M. et al. The nuclear effector of Wnt-signaling, Tcf1, functions as a T-cell-specific tumor suppressor for development of lymphomas. PLoS Biol. 10, e1001430 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yu, S. et al. The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy. Immunity 37, 813–826 (2012). References 88 and 89 show the complex intra-family relationships between TCF1 and LEF1 in early T cell development, and the importance of certain isoforms of TCF1 that function as tumour suppressors by repressing the expression of Lef1.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Schilham, M. W. et al. Critical involvement of Tcf-1 in expansion of thymocytes. J. Immunol. 161, 3984–3991 (1998).

    CAS  PubMed  Google Scholar 

  91. Staal, F. J. T. & Sen, J. M. The canonical Wnt signaling pathway plays an important role in lymphopoiesis and hematopoiesis. Eur. J. Immunol. 38, 1788–1794 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Dose, M. et al. β-Catenin induces T-cell transformation by promoting genomic instability. Proc. Natl Acad. Sci. USA 111, 391–396 (2014).

    CAS  PubMed  Google Scholar 

  93. Giese, K., Kingsley, C., Kirshner, J. R. & Grosschedl, R. Assembly and function of a TCRα enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev. 9, 995–1008 (1995).

    CAS  PubMed  Google Scholar 

  94. Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hosoya, T., Maillard, I. & Engel, J. D. From the cradle to the grave: activities of GATA-3 throughout T-cell development and differentiation. Immunol. Rev. 238, 110–125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ho, I. C., Tai, T. S. & Pai, S. Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nature Rev. Immunol. 9, 125–135 (2009).

    CAS  Google Scholar 

  97. García-Ojeda, M. E. et al. GATA-3 promotes T cell specification by repressing B cell potential in pro-T cells. Blood 121, 1749–1759 (2013). This paper identifies GATA3 as the crucial intrinsic regulatory factor in the earliest T cell lineage precursor cells that is responsible for excluding access to the B cell lineage.

    PubMed  Google Scholar 

  98. Tan, J. B., Visan, I., Yuan, J. S. & Guidos, C. J. Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nature Immunol. 6, 671–679 (2005).

    CAS  Google Scholar 

  99. Sambandam, A. et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunol. 6, 663–670 (2005).

    CAS  Google Scholar 

  100. Pai, S. Y. et al. Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19, 863–875 (2003).

    CAS  PubMed  Google Scholar 

  101. Hosoya-Ohmura, S. et al. An NK and T cell enhancer lies 280 kilobase pairs 3′ to the Gata3 structural gene. Mol. Cell. Biol. 31, 1894–1904 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Weishaupt, H., Sigvardsson, M. & Attema, J. L. Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells. Blood 115, 247–256 (2010).

    CAS  PubMed  Google Scholar 

  103. Vigano, M. A. et al. An epigenetic profile of early T-cell development from multipotent progenitors to committed T-cell descendants. Eur. J. Immunol. 44, 1181–1193 (2014).

    CAS  PubMed  Google Scholar 

  104. Xu, W. et al. E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood 121, 1534–1542 (2013). This paper reveals that GATA3 activity must be kept under inhibitory restraint by the same bHLH E proteins that also collaborate with it to drive T cell specification. This is shown to be one important way in which E2A promotes successful T cell commitment.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Xu, W. & Kee, B. L. Growth factor independent 1B (Gfi1b) is an E2A target gene that modulates Gata3 in T-cell lymphomas. Blood 109, 4406–4414 (2007).

    CAS  PubMed  Google Scholar 

  106. Maneechotesuwan, K. et al. Regulation of TH2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J. Immunol. 178, 2491–2498 (2007).

    CAS  PubMed  Google Scholar 

  107. Cook, K. D. & Miller, J. TCR-dependent translational control of GATA-3 enhances TH2 differentiation. J. Immunol. 185, 3209–3216 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Frelin, C. et al. GATA-3 regulates the self-renewal of long-term hematopoietic stem cells. Nature Immunol. 14, 1037–1044 (2013).

    CAS  Google Scholar 

  109. Wei, G. et al. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35, 299–311 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Okamura, R. M. et al. Redundant regulation of T cell differentiation and TCRβ gene expression by the transcription factors LEF-1 and TCF-1. Immunity 8, 11–20 (1998).

    CAS  PubMed  Google Scholar 

  111. Wojciechowski, J., Lai, A., Kondo, M. & Zhuang, Y. E2A and HEB are required to block thymocyte proliferation prior to pre-TCR expression. J. Immunol. 178, 5717–5726 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhong, Y., Jiang, L., Hiai, H., Toyokuni, S. & Yamada, Y. Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice. Oncogene 26, 6937–6947 (2007).

    CAS  PubMed  Google Scholar 

  113. Welinder, E. et al. The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor. Proc. Natl Acad. Sci. USA 108, 17402–17407 (2011).

    CAS  PubMed  Google Scholar 

  114. Schwartz, R., Engel, I., Fallahi-Sichani, M., Petrie, H. T. & Murre, C. Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development. Proc. Natl Acad. Sci. USA 103, 9976–9981 (2006).

    CAS  PubMed  Google Scholar 

  115. Takeuchi, A. et al. E2A and HEB activate the pre-TCRα promoter during immature T cell development. J. Immunol. 167, 2157–2163 (2001).

    CAS  PubMed  Google Scholar 

  116. Ikawa, T. et al. An essential developmental checkpoint for production of the T cell lineage. Science 329, 93–96 (2010).

    CAS  PubMed  Google Scholar 

  117. Li, L., Leid, M. & Rothenberg, E. V. An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 329, 89–93 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Li, P. et al. Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329, 85–89 (2010). References 116–118 define the role of Bcl11b in T cell lineage commitment.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cismasiu, V. B. et al. BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter. Oncogene 24, 6753–6764 (2005).

    CAS  PubMed  Google Scholar 

  120. Li, L. et al. A far downstream enhancer for murine Bcl11b controls its T-cell specific expression. Blood 122, 902–911 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Guo, Y., Maillard, I., Chakraborti, S., Rothenberg, E. V. & Speck, N. A. Core binding factors are necessary for natural killer cell development, and cooperate with Notch signaling during T cell specification. Blood 112, 480–492 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Kastner, P. et al. Bcl11b represses a mature T-cell gene expression program in immature CD4+CD8+ thymocytes. Eur. J. Immunol. 40, 2143–2154 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Oosterwegel, M. et al. Cloning of murine TCF-1, a T cell-specific transcription factor interacting with functional motifs in the CD3-ɛ and T cell receptor α enhancers. J. Exp. Med. 173, 1133–1142 (1991).

    CAS  PubMed  Google Scholar 

  124. Yashiro-Ohtani, Y. et al. Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A. Genes Dev. 23, 1665–1676 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Lauritsen, J. P. et al. Marked induction of the helix-loop-helix protein Id3 promotes the γδ T cell fate and renders their functional maturation Notch independent. Immunity 31, 565–575 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Wakabayashi, Y. et al. Bcl11b is required for differentiation and survival of αβ T lymphocytes. Nature Immunol. 4, 533–539 (2003).

    CAS  Google Scholar 

  127. Inoue, J. et al. Expression of TCRαβ partly rescues developmental arrest and apoptosis of αβ T cells in Bcl11b−/− mice. J. Immunol. 176, 5871–5879 (2006).

    CAS  PubMed  Google Scholar 

  128. Shibata, K. et al. IFN-γ-producing and IL-17-producing γδ T cells differentiate at distinct developmental stages in murine fetal thymus. J. Immunol. 192, 2210–2218 (2014).

    CAS  PubMed  Google Scholar 

  129. Barndt, R. J., Dai, M. & Zhuang, Y. Functions of E2A–HEB heterodimers in T-cell development revealed by a dominant negative mutation of HEB. Mol. Cell. Biol. 20, 6677–6685 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Winandy, S., Wu, L., Wang, J. H. & Georgopoulos, K. Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J. Exp. Med. 190, 1039–1048 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ciofani, M. & Zúñiga-Pflücker, J. C. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nature Immunol. 6, 881–888 (2005).

    CAS  Google Scholar 

  132. Schjerven, H. et al. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nature Immunol. 14, 1073–1083 (2013).

    CAS  Google Scholar 

  133. Zhang, J. et al. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nature Immunol. 13, 86–94 (2012).

    CAS  Google Scholar 

  134. Chari, S. & Winandy, S. Ikaros regulates Notch target gene expression in developing thymocytes. J. Immunol. 181, 6265–6274 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kleinmann, E., Geimer Le Lay, A. S., Sellars, M., Kastner, P. & Chan, S. Ikaros represses the transcriptional response to Notch signaling in T-cell development. Mol. Cell. Biol. 28, 7465–7475 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Geimer Le Lay, A. S. et al. The tumor suppressor Ikaros shapes the repertoire of Notch target genes in T cells. Sci. Signal. 7, ra28 (2014).

    PubMed  Google Scholar 

  137. Tussiwand, R. et al. The preTCR-dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL-7 signaling. Eur. J. Immunol. 41, 3371–3380 (2011).

    CAS  PubMed  Google Scholar 

  138. Janas, M. L. et al. Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4. J. Exp. Med. 207, 247–261 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Xi, H., Schwartz, R., Engel, I., Murre, C. & Kersh, G. J. Interplay between RORγt, Egr3, and E proteins controls proliferation in response to pre-TCR signals. Immunity 24, 813–826 (2006).

    CAS  PubMed  Google Scholar 

  140. Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Ciofani, M. et al. A validated regulatory network for TH17 cell specification. Cell 151, 289–303 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. He, Y. W. et al. Down-regulation of the orphan nuclear receptor RORγt is essential for T lymphocyte maturation. J. Immunol. 164, 5668–5674 (2000).

    CAS  PubMed  Google Scholar 

  143. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    CAS  PubMed  Google Scholar 

  144. Wang, R. et al. Transcription factor network regulating CD4+CD8+ thymocyte survival. Crit. Rev. Immunol. 31, 447–458 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Pongracz, J. E., Parnell, S. M., Jones, T., Anderson, G. & Jenkinson, E. J. Overexpression of ICAT highlights a role for catenin-mediated canonical Wnt signalling in early T cell development. Eur. J. Immunol. 36, 2376–2383 (2006).

    CAS  PubMed  Google Scholar 

  146. Xu, M., Sharma, A., Wiest, D. L. & Sen, J. M. Pre-TCR-induced β-catenin facilitates traversal through β-selection. J. Immunol. 182, 751–758 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Xu, M., Sharma, A., Hossain, M. Z., Wiest, D. L. & Sen, J. M. Sustained expression of pre-TCR induced β-catenin in post-β-selection thymocytes blocks T cell development. J. Immunol. 182, 759–765 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Schroeder, J. H., Bell, L. S., Janas, M. L. & Turner, M. Pharmacological inhibition of glycogen synthase kinase 3 regulates T cell development in vitro. PLoS ONE 8, e58501 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Aifantis, I., Raetz, E. & Buonamici, S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nature Rev. Immunol. 8, 380–390 (2008).

    CAS  Google Scholar 

  150. Uckun, F. M. et al. Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study. J. Clin. Oncol. 15, 2214–2221 (1997).

    CAS  PubMed  Google Scholar 

  151. Ferrando, A. A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).

    CAS  PubMed  Google Scholar 

  152. Van Vlierberghe, P. et al. Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. Blood 122, 74–82 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Smith, S. et al. LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways. PLoS ONE 9, e85883 (2014).

    PubMed  PubMed Central  Google Scholar 

  154. Haydu, J. E. & Ferrando, A. A. Early T-cell precursor acute lymphoblastic leukaemia. Curr. Opin. Hematol. 20, 369–373 (2013).

    CAS  PubMed  Google Scholar 

  155. Van de Walle, I. et al. An early decrease in Notch activation is required for human TCR-αβ lineage differentiation at the expense of TCR-γδ T cells. Blood 113, 2988–2998 (2009).

    CAS  PubMed  Google Scholar 

  156. Joachims, M. L., Chain, J. L., Hooker, S. W., Knott-Craig, C. J. & Thompson, L. F. Human αβ and γδ thymocyte development: TCR gene rearrangements, intracellular TCR β expression, and γδ developmental potential — differences between men and mice. J. Immunol. 176, 1543–1552 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Blom, B. & Spits, H. Development of human lymphoid cells. Annu. Rev. Immunol. 24, 287–320 (2006).

    CAS  PubMed  Google Scholar 

  158. Aster, J. C., Blacklow, S. C. & Pear, W. S. Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. J. Pathol. 223, 262–273 (2011).

    CAS  PubMed  Google Scholar 

  159. Tremblay, C. S. & Hoang, T. Early T cell differentiation lessons from T-cell acute lymphoblastic leukemia. Prog. Mol. Biol. Transl. Sci. 92, 121–156 (2010).

    CAS  PubMed  Google Scholar 

  160. Winandy, S., Wu, P. & Georgopoulos, K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 83, 289–299 (1995).

    CAS  PubMed  Google Scholar 

  161. Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    CAS  PubMed  Google Scholar 

  162. Laurenti, E. et al. The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nature Immunol. 14, 756–763 (2013).

    CAS  Google Scholar 

  163. Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nature Med. 18, 298–301 (2012).

    CAS  PubMed  Google Scholar 

  164. Neumann, M. et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood 121, 4749–4752 (2013).

    CAS  PubMed  Google Scholar 

  165. Cleveland, S. M. et al. Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia. Stem Cells 31, 882–894 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Treanor, L. M. et al. Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential. J. Exp. Med. 211, 701–713 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Yui, M. A. et al. Loss of T cell progenitor checkpoint control underlies leukemia initiation in Rag1-deficient nonobese diabetic mice. J. Immunol. 190, 3276–3288 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Yui, M. A. & Rothenberg, E. V. Deranged early T cell development in immunodeficient strains of nonobese diabetic mice. J. Immunol. 173, 5381–5391 (2004).

    CAS  PubMed  Google Scholar 

  169. Litman, G. W., Anderson, M. K. & Rast, J. P. Evolution of antigen binding receptors. Annu. Rev. Immunol. 17, 109–147 (1999).

    CAS  PubMed  Google Scholar 

  170. Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nature Rev. Immunol. 13, 88–100 (2013).

    CAS  Google Scholar 

  171. Kang, J., Volkmann, A. & Raulet, D. H. Evidence that γδ versus αβ T cell fate determination is initiated independently of T cell receptor signaling. J. Exp. Med. 193, 689–698 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Melichar, H. J. et al. Regulation of γδ versus αβ T lymphocyte differentiation by the transcription factor SOX13. Science 315, 230–233 (2007).

    CAS  PubMed  Google Scholar 

  173. Feng, N., Vegh, P., Rothenberg, E. V. & Yui, M. A. Lineage divergence at the first TCR-dependent checkpoint: preferential γδ and impaired αβ T cell development in nonobese diabetic mice. J. Immunol. 186, 826–837 (2011).

    CAS  PubMed  Google Scholar 

  174. Van de Walle, I. et al. Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength. J. Exp. Med. 210, 683–697 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Haks, M. C. et al. Attenuation of γδTCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22, 595–606 (2005).

    CAS  PubMed  Google Scholar 

  176. Hayes, S. M., Li, L. & Love, P. E. TCR signal strength influences αβ/γδ lineage fate. Immunity 22, 583–593 (2005).

    CAS  PubMed  Google Scholar 

  177. Narayan, K. et al. Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes. Nature Immunol. 13, 511–518 (2012).

    CAS  Google Scholar 

  178. Verykokakis, M. et al. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor protein-dependent “innate” γδ T cells. PLoS ONE 5, e9303 (2010).

    PubMed  PubMed Central  Google Scholar 

  179. Kreslavsky, T. et al. TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity. Proc. Natl Acad. Sci. USA 106, 12453–12458 (2009).

    CAS  PubMed  Google Scholar 

  180. Kreslavsky, T. Gleimer, M. & von Boehmer, H. αβ versus γδ lineage choice at the first TCR-controlled checkpoint. Curr. Opin. Immunol. 22, 185–192 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Prinz, I., Silva-Santos, B. & Pennington, D. J. Functional development of γδ T cells. Eur. J. Immunol. 43, 1988–1994 (2013).

    CAS  PubMed  Google Scholar 

  182. Schlenner, S. M. & Rodewald, H. R. Early T cell development and the pitfalls of potential. Trends Immunol. 31, 303–310 (2010).

    CAS  PubMed  Google Scholar 

  183. Richie Ehrlich, L. I., Serwold, T. & Weissman, I. L. In vitro assays misrepresent in vivo lineage potentials of murine lymphoid progenitors. Blood 117, 2618–2624 (2011).

    PubMed  PubMed Central  Google Scholar 

  184. Benz, C. & Bleul, C. C. A multipotent precursor in the thymus maps to the branching point of the T versus B lineage decision. J. Exp. Med. 202, 21–31 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Laiosa, C. V., Stadtfeld, M., Xie, H., de Andres-Aguayo, L. & Graf, T. Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors. Immunity 25, 731–744 (2006).

    CAS  PubMed  Google Scholar 

  186. Wölfler, A. et al. Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors. Blood 116, 4116–4125 (2010).

    PubMed  Google Scholar 

  187. Franco, C. B. et al. Notch/Delta signaling constrains reengineering of pro-T cells by PU.1. Proc. Natl Acad. Sci. USA 103, 11993–11998 (2006).

    CAS  PubMed  Google Scholar 

  188. Huang, G. et al. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nature Genet. 40, 51–60 (2008).

    CAS  PubMed  Google Scholar 

  189. Zarnegar, M. A., Chen, J. & Rothenberg, E. V. Cell-type-specific activation and repression of PU.1 by a complex of discrete, functionally specialized cis-regulatory elements. Mol. Cell. Biol. 30, 4922–4939 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Rosenbauer, F. et al. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nature Genet. 38, 27–37 (2006).

    CAS  PubMed  Google Scholar 

  191. Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Yang, Q. et al. T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38, 694–704 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Gentek, R. et al. Modulation of signal strength switches Notch from an inducer of T cells to an inducer of ILC2. Front. Immunol. 4, 334 (2013).

    PubMed  PubMed Central  Google Scholar 

  194. Heng, T. S. P., Painter, M. W. & The Immunological Genome Project Consortium. The Immunological Genome Project: networks of gene expression in immune cells. Nature Immunol. 9, 1091–1094 (2008).

    CAS  Google Scholar 

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Acknowledgements

The authors apologize to colleagues whose work helped to inspire this Review but could not be cited due to space constraints. The authors thank present and former members of their group whose published and unpublished data, as well as helpful discussion, shaped the ideas presented here. The authors gratefully acknowledge support from the US National Institutes of Health (NIH grant AI064590 to M.A.Y., and AI083514, AI095943 and HD076915 to E.V.R.) and the Albert Billings Ruddock Professorship (to E.V.R).

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Supplementary information S1 (Table)

Critical T cell specification transcription factor genes in murine early T cells and their progenitors (PDF 638 kb)

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Critical phase 1-specific transcription factor genes in murine early T cells and their progenitors (PDF 633 kb)

Glossary

Commitment

The stage at which cells give up their intrinsic capability to produce more than one kind of descendant. This concept depends on recognizing that precursor cells begin with the intrinsic potential to give rise to various different types of descendant, but the actual fate choices that such precursor cells adopt will be different depending on the signals that they receive from the environment. Commitment is the developmental transition within a given pathway during which the chosen cell fate becomes intrinsically irreversible, independent of the environment.

Gene regulatory network

A system of relationships between a set of regulatory genes and the transcription factors that they encode, which is defined such that the interactions between them explain the stability or change in the developmental properties of a cell type that expresses those genes.

Notch signalling

A signalling system comprised of highly conserved transmembrane receptors that regulate cell fate choice in the development of many cell lineages and are thus crucial for the regulation of embryonic differentiation and development. Unusually among signalling systems, the cytoplasmic domain of each Notch transmembrane protein can itself become a transcriptional co-activator in the nucleus, as it can be proteolytically cleaved from the transmembrane region when Notch interacts with its ligands of the Delta or Jagged family.

T cell acute lymphoblastic leukaemia

(T-ALL). Leukaemia with an immature T cell phenotype.

Common lymphoid precursors

(CLPs). These are a type of progenitor cell that seems to be committed to lymphoid fates (as measured by in vivo transfer) and that can give rise to all lymphoid cell types, including T cells, B cells and natural killer cells.

Lymphoid-primed multipotent precursors

(LMPPs). These are multilineage precursor cells that can generate myeloid and lymphoid descendants in vivo and in vitro but that cannot generate erythroid or megakaryocytic cells.

Positive selection

A step in the process of T cell differentiation in the thymus that selects CD4+CD8+ double-positive T cells for survival and maturation, on the basis of the appropriate degree of interaction between their T cell receptor and the peptide—MHC complexes that are expressed on thymic epithelial cells. Depending on the class of MHC molecule that is recognized, thymocytes are positively selected to a CD4+ or a CD8+ single-positive cell fate.

Pioneer factor

A transcription factor that has the ability to bind to its target site even when the site is initially located within nucleosome-packed chromatin, thus serving as a focal point for the recruitment of other transcription factors. Pioneer factors are crucial for the multi-step process that is needed to activate some positive regulatory elements in the genome during development.

WNT

A signalling mediator named both for its mutant phenotype in Drosophila melanogaster (Wingless) and for its role as a preferential retrovirus integration site in murine leukaemia virus-induced leukaemias (Int-1). WNT signalling activates the T cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1) family transcription factors through stabilizing their co-activator, β-catenin, and mobilizing it from the cytoplasm to the nucleus.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). A genome-wide method of mapping the sites at which a transcription factor binds to the DNA in a cell, that involves crosslinking proteins to chromatin, immunoprecipitating the chromatin with antibodies specific for the factor of interest, comprehensively sequencing the DNA that is recovered in the immunoprecipitates and aligning the obtained sequences with the genome to identify the enriched regions.

Non-obese diabetic mice

(NOD mice). These mice spontaneously develop type 1 (insulin-dependent) diabetes mellitus as a result of autoreactive T cell-mediated destruction of pancreatic β-islet cells.

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Yui, M., Rothenberg, E. Developmental gene networks: a triathlon on the course to T cell identity. Nat Rev Immunol 14, 529–545 (2014). https://doi.org/10.1038/nri3702

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